AIDS has emerged as a significant pediatric disease with the rate of infection in neonates born to HIV-infected mothers reported to be from 20- 50%. The clinical disease that occurs in HIV-infected infants is similar to the adult, although pediatric AIDS has a more rapid clinical course with a higher rate of mortality. About one-third of HIV-infected infants have a rapidly fatal disease course and die within l year; remaining infants develop clinical disease more slowly and survive for more than five years. The timing of vertical transmission, levels or type of maternal antiviral antibodies and, transmission of distinct maternal viral variants have been proposed to explain this bimodal pattern of disease progression, with the more rapid, severe outcome associated with prenatal infection, and due to transmission of highly pathogenic virus strains. HIV-infected children are frequently small-for-gestational-age or growth- restricted, and continue to exhibit poor weight gain and growth throughout infancy and childhood. Failure-to-thrive constitutes a cardinal feature of pediatric AIDS. Few studies have assessed the role of growth factors such as insulin-like growth factor (IGF-I) in HIV-infected children although reports have suggested deficiencies may play a major role in growth failure and disease progression. Studies with the SIV-infected fetal monkey have shown that inoculation of fetal macaques in utero with pathogenic SlVmac during the early 2nd trimester consistently results in intrauterine growth retardation/restriction (IUGR), oligohydramnios, and a rapid postnatal disease course, whereas inoculation with a nonpathogenic molecular clone (SIVmac1A11) does not affect growth or result in disease. Evaluations of sera from (pathogenic) SIV-infected fetuses have shown a disruption of the IGF axis: IGF-I is significantly diminished while IGF binding protein (IGFBP-3) is significantly elevated. Based on these data we hypothesize that the high virus load associated with pathogenic SIV infection but not nonpathogenic SIV infection in utero results in a perturbation of the fetal IGF axis, with subsequent effects on pre- and postnatal growth. Studies are proposed which will characterize the role of the IGF axis in fetal (pathogenic and nonpathogenic) SIV infection while exploring methods for reversing aberrant growth patterns and disease progression by administering IGF-I and antiretrovirals such as AZT to SIV- infected fetuses and infants (Specific Aim 1). We will examine the interactions between virus load, fetal growth factors (IGF-I, IGF-II), receptors, and serum carrier proteins during development, and study immune response and clinical indicators of fetal/neonatal compromise and disease. Since the best supportive care has not been able to alter the growth failure characteristic of pediatric AIDS, and because aberrant growth patterns are correlated with decreased survival, there is an urgent need to define the role of growth factors such as IGF-I and to assess methods for early intervention. These investigations will provide essential information on fetal growth in health and disease using a well-defined SIV-infected pediatric monkey model which will be directly applicable to the human fetus and infant infected with HIV.